Pharmacology: Antitumor activity: This product has effects to inhibit the growth of tumors such as Walker-256 carcinosarcoma, Yoshida's sarcoma, ascitis carcinoma (in rats), Sarcoma-180, Ehrlich's carcinoma, Lewis's lung arcinoma, and B-16metanoma (in mice) transplanted subcutaneously. This product also has effects to inhibit the growth of human cancers such as gastric, beast, and pancreatic when transplanted subcutaneously to nude mice. This product also has survival effects in animals (mice) bearing L-1210 transplanted leukemia.
Mechanism of action: The antitumor activity of this product is based on 5-FU that appears gradually in the body via the transformation of tegafur. The action mechanism of 5-FU is considered to be inhibition of DNA synthesis resulting from the antagonistic effect of the active metabolite FdUMP, which antagonize dUMP and inhibit thymidylate synthase. The function of RNA will be disordered according to the incorporation of FUTP into RNA (in vitro study). Uracil, when combined with tegafur, enhances the tegafur's antitumor activity. Because 5-FU degradation is depressed by the difference of affinities to phosphorylative or degradative enzymes between 5-FU and uracil, concentrations of 5-FU and its phosphorylated active metabolite can be highly maintained in tumor tissues (in vitro).
Pharmacokinetics: Three capsules of this product (corresponding to 300 mg as tegafur were orally administered to cancer patients, and the blood level of tegafur was maximum of 13.7±1.1 μg/ml at 2 hours, which then fell gradually to 3.6±0.8 μg/ml at 24 hours postadministration. The mean blood levels of 5-FU and uracil were a maximum of 0.21± 0.094 μg/ml and 3.0±1.8 μg/ml at 30 minutes, respectively. The level of 5-FU then fell to 0.05±0.019 μg/ml at three hours, and the level of uracil fell to 0.30 ± 0.23 μg/ml at six hours after administration.
Conversely, the levels of 5-FU in the blood, tumor tissues, and normal tissues adjacent to the tumors postadministration of the product were comparatively determined, from which it was realized that the 5-FU level in the tumors was the highest.
Folinate plus Tegafur-Uracil combination therapy: Influence of meals: In a cross-over trial with cancer patients, folinate (30 mg) and Tegafur-Uracil (equiv. 200 mg tegafur) were administered during fasting or after meal (high-fat diet). In post-prandial administration, the AUCs for Uracil and tegafur-derived fluorouracil were lower by 66% and 37%, respectively, than in fasting administration, while AUC for folinate was higher by 61%. The AUC of tegafur, on the other hand, showed no significant difference.